View source for GP1 of Lassa Virus

<StructureSection load='4zjf' size='340' side='right' caption='Glycosylated receptor binding domain of Lassa Virus (PDB code [[4zjf]])' scene='76/761695/4zjf_chaina/4'>
==Importance==
Lassa virus (LASV), an Old World (OW) [http://en.wikipedia.org/wiki/Arenavirus arenavirus], is a notorious disease-causing agent primarily in West Africa that is able to spread from rodents to humans. This deadly pathogen causes severe viral hemorrhagic fevers and significant mortality. So far, there are no available vaccines for LASV, and only one successful vaccine against another virus found in the ''Arenaviridae'' family: Junin virus<ref name="PMID: 9466512">PMID: 9466512 </ref>. Structural data at atomic resolution for viral proteins are laying the foundation for better understanding both the biology behind viral proteins and ways to combat against them. Determining the structure of the complete trimeric glycoprotein complex (GPC), composed of GP1, GP2, and SSP (stable signal peptide), will pave the path towards a future discovery of novel antiviral drugs. This is the first representative structure for OW arenaviruses. This structure reveals the overall architecture of GP1 domains from OW arenaviruses and important information relating to the mechanisms for pH switching and the binding of LASV to [[LAMP1]] (Lysosome-associated membrane glycoprotein), a recently identified host receptor that is critical for successful infection. In addition, structural analysis suggests two novel immune evasion mechanisms that LASV may utilize to escape antibody-based immune response.
== Function ==
'''GP1''' (Glycoprotein 1) is the receptor binding domain of LASV that mediates receptor recognition. Research thus far indicates that GP1 from LASV may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Arenaviruses utilize various cell surface proteins as their cellular receptors for recognizing and attaching to target cells. New World (NW) arenaviruses that belong to clades A and B use transferrin receptor 1 (TfR1)<ref name="PMID:17287727">PMID:17287727</ref><ref name="PMID:24920811">PMID:24920811</ref>, whereas OW arenaviruses, as well as clade C NW arenaviruses, use α-dystroglycan (α-DG) <ref name="PMID:9851928">PMID:9851928</ref><ref name="PMID:15857984">PMID:15857984</ref><ref name="PMID:11967329">PMID:11967329</ref>. A trimeric class 1 viral glycoprotein complex (the spike complex) recognizes the cellular receptors and mediates membrane fusion upon exposure to low pH at the lysosome <ref name="PMID:16731928">PMID:16731928</ref>. The spike complex is expressed as a glycoprotein precursor that is cleaved into three segments by a signal peptidase and SKI-1/S1P protease<ref name="PMID:21612810">PMID:21612810</ref>. The functional spike complex consists of GP1, a membrane-anchored fusion protein (GP2), and a unique structured SSP <ref name="PMID:23202458">PMID:23202458</ref>.                                                                                                                                                                                                                                                                                                                                                                                         
==Structural Highlights==
GP1 of LASV is a single chain structure with attached <scene name='76/761695/Nag/4'>NAG</scene> glycans. The overall architecture of GP1 features a central β-sheet and two distinct halves: a glycosylated half containing the receptor-binding site that is made mostly by the central β-sheet and surrounding loops and a half that contains mostly helices and most likely faces the trimer axis<ref name="PMID: 25972533">PMID: 25972533</ref>, as determined in the [http://www.weizmann.ac.il/Structural_Biology/diskin Diskin laboratory] at the Weizmann Institute of Science. The method used to determine this structure was [http://en.wikipedia.org/wiki/X-ray_crystallography X-ray diffraction]
===LAMP1 Binding Site===
The primary cellular receptor of LASV is α-dystroglycan (α-DG)<ref name="PMID: 9851928">PMID: 9851928</ref><ref name="PMID: 15857984">PMID: 15857984</ref>, which is recognized by a trimeric class 1 viral GPC (spike complex) on the viral surface<ref name="PMID: 16731928">PMID: 16731928</ref><ref name="PMID: 26849049">PMID: 26849049</ref>. Following successful attachment to α-DG on cells, LASV is internalized via [http://en.wikipedia.org/wiki/Pinocytosis macropinocytosis]<ref name="PMID: 27147735">PMID: 27147735</ref>, and the GPC facilitates membrane fusion at the acidic environment of a late endosomal compartment<ref name="PMID: 16731928"><ref name="PMID: 21931550">PMID: 21931550 </ref>. Recent studies have shown that successful infection by LASV requires it to switch in a pH-dependent manner from α-DG to LAMP1<ref name="PMID: 27605678" /><ref name="PMID:24970085">PMID:24970085</ref>. Binding of the <scene name='76/761695/Lamp1bindingsite/14'>LAMP1</scene> endosomal compartment triggers the spikes.
=== Histidine Triad===
Included in this structure is a unique <scene name='76/761695/Histriad/9'>triad of histidines</scene> that is highly conserved among OW arenaviruses. Located on the β-sheet face of GP1,  the histidine triad is a structural element that directly interacts with LAMP1 and helps stabilize a LAMP1-"compatible" conformation by providing a molecular mechanism for the pH-dependent receptor switching<ref name="PMID: 25972533" />. The <scene name='76/761695/Lamp1bindingsite/15'>histidine triad</scene> is critical in forming a <scene name='76/761695/Lamp1bindingsite/16'>binding site</scene> for LAMP1<ref name="PMID: 27605678">PMID: 27605678 </ref><ref name="PMID: 28448640">PMID: 28448640 </ref>.
==Resources==
For more information on this protein structure visit the following sites: [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zjf OCA], [http://pdbe.org/4zjf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zjf RCSB], [http://www.ebi.ac.uk/pdbsum/4zjf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zjf ProSAT]
</StructureSection>
== References ==
<references/>
[[Category: Cohen, N]]
[[Category: Cohen-Dvashi, H]]
[[Category: Diskin, R]]
[[Category: Israeli, H]]
[[Category: Arenavirus]]
[[Category: Glycoprotein]]
[[Category: Lassa]]
[[Category: LASV]]
[[Category: Receptor binding]]
[[Category: Viral protein]]
[[Category: 4zjf]]
[[Category: GP1]]